PROJECT SUMMARY/ABSTRACT The overall objective of this fellowship proposal is to evaluate the role of Cold inducible RNA binding protein (CIRP) in breast cancer and inflammation. Our studies support a role for CIRP as a potent anti-tumor molecule and decreases pro-tumorigenic inflammation in breast cancer in vivo. More specifically, CIRP impedes breast tumorigenesis and metastasis in the PyMT mouse model for breast cancer. To begin to assess mechanism, mammary glands were taken from 7-week old mice and incubated in media overnight followed by Luminex cytokine assays. Results show a decrease in cytokines that promote pro-tumorigenic inflammation, angiogenesis, and metastasis. The central hypothesis to be tested is that CIRP impedes breast tumorigenesis through promotion of an acute inflammatory response and/or by inhibiting a pro-tumorigenic inflammatory response. The following specific aims will be pursued: Specific Aim 1: Examine the effects of CIRP overexpression on tumorigenesis, inflammatory cytokines and inflammatory cells in vivo. Specific Aim 2: Examine the effect of CIRP loss on tumorigenesis in vivo. Specific Aim 3: Correlate CIRP expression with inflammation in matched human normal and breast cancer tissues and in patient sera. Hypothesis: CIRP impedes breast tumorigenesis by decreasing pro-tumorigenic inflammatory cytokines. CIRP loss will loss will increase tumor growth kinetics, total tumor burden and pro-tumorigenic inflammatory cytokines. CIRP expression in human breast cancer will correlate with lower tumorigenicity, lower levels of pro-tumorigenic inflammatory cytokines, as well as the signature for good prognosis in breast cancer (CD68lo CD4lo CD8hi). Experiments are designed to clarify the molecular basis of CIRP?s actions in pre-clinical mouse models along with human breast cancer samples. Indices of tumorigenesis will be measured such as onset, neoplastic burden (early time point), tumor area, total tumor burden and number of pulmonary metastases. Also, experiments will assess levels of inflammatory cytokines as well as which lymphocytes and innate immune cells are secreting them. This research is innovative because it is expected to elucidate CIRP?s role as a novel tumor suppressor in vivo, using the first transgenic mouse that overexpresses CIRP in the mammary gland. Furthermore, elucidating CIRP?s role as an inflammatory modulator may reveal a target for novel therapeutics potential to enhance its tumor suppressive activity.